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Protein Phosphatase 2A Subunit PR70 Interacts with pRb and Mediates Its Dephosphorylation

机译：蛋白磷酸酶2A亚基PR70与pRb相互作用并介导其去磷酸化

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The retinoblastoma tumor suppressor protein (pRb) regulates cell proliferation and differentiation via phosphorylation-sensitive interactions with specific targets. While the role of cyclin/cyclin-dependent kinase complexes in the modulation of pRb phosphorylation has been extensively studied, relatively little is known about the molecular mechanisms regulating phosphate removal by phosphatases. Protein phosphatase 2A (PP2A) is constituted by a core dimer bearing catalytic activity and one variable B regulatory subunit conferring target specificity and subcellular localization. We previously demonstrated that PP2A core dimer binds pRb and dephosphorylates pRb upon oxidative stress. In the present study, we identified a specific PP2A-B subunit, PR70, that was associated with pRb both in vitro and in vivo. PR70 overexpression caused pRb dephosphorylation; conversely, PR70 knockdown prevented both pRb dephosphorylation and DNA synthesis inhibition induced by oxidative stress. Moreover, we found that intracellular Ca2+ mobilization was necessary and sufficient to trigger pRb dephosphorylation and PP2A phosphatase activity of PR70 was Ca2+ induced. These data underline the importance of PR70-Ca2+ interaction in the signal transduction mechanisms triggered by redox imbalance and leading to pRb dephosphorylation.
机译：视网膜母细胞瘤抑癌蛋白（pRb）通过与特定靶标的磷酸化敏感相互作用调节细胞增殖和分化。尽管已经广泛研究了细胞周期蛋白/细胞周期蛋白依赖性激酶复合物在调节pRb磷酸化中的作用，但有关调节磷酸酶去除磷酸盐的分子机制知之甚少。蛋白磷酸酶2A（PP2A）由具有催化活性的核心二聚体和一个赋予目标特异性和亚细胞定位的可变B调节亚基组成。我们先前证明，PP2A核心二聚体在氧化应激后会结合pRb并使pRb脱磷酸。在本研究中，我们鉴定了一个特定的PP2A-B亚基PR70，它在体外和体内均与pRb相关。 PR70过表达引起pRb去磷酸化;相反，PR70的组合可防止pRb去磷酸化和氧化应激诱导的DNA合成抑制。此外，我们发现细胞内Ca 2 + 的动员是必要且足以触发pRb去磷酸化的，PR70的PP2A磷酸酶活性是由Ca 2 + 诱导的。这些数据强调了PR70-Ca 2 + 相互作用在氧化还原不平衡触发并导致pRb去磷酸化的信号转导机制中的重要性。

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